A prognostic hypoxia gene signature is associated with a dampened tumour immune microenvironment in cervical cancer

Abstract

Background: Hypoxia, or low oxygen, is a condition that is characteristic of solid tumours, including cervical cancer. Hypoxia is associated with worse survival in this disease and supports tumorigenic characteristics of stemness, survival, metastasis and angiogenesis, as well as immune resistance. Aims: In this work, we aimed to determine the prognostic significance of a previously derived in vitro eight-gene hypoxia signature in cervical cancer, and to investigate the interplay between the hypoxic and immune features of the cervical tumour microenvironment (TME). Subjects and Methods: The 240 patients with cervical squamous cell carcinoma obtained from the Cancer Genome Atlas Pan-Cancer study were first given a hypoxia score and an immune score (IS) and subsequently subjected to survival analysis. CIBERSORTx was also applied to determine the fractions of immune cells residing in the hypoxia high versus hypoxia low patient groups. Results: We show that the eight-gene hypoxia signature is predictive of worse prognosis in patients with cervical cancer and is associated with a less immunogenic TME. Furthermore, by combining the hypoxia score with an IS to stratify patients based on both their hypoxic and immune status, we achieve an enhancement in survival prediction, with the hypoxia high/immune low subgroup of patients showing the worse probability of overall and disease-specific survival. Conclusions: It is clear from this work that the interplay between the hypoxic and immune microenvironment can contribute to cervical cancer patients' survival. Furthermore, patients with tumours that are both highly hypoxic and immune deprived should be considered for hypoxia-targeted therapy when planning treatment modalities to improve survival.